Project Summary/Abstract HAT (hydrogen atom transfer) alkene reactions offer the opportunity to functionalize unactivated alkenes under mild conditions, creating highly substituted carbon sites that are prevalent in biologically active molecules. However, the rational design of catalysts for HAT alkene reactions with higher yield, faster rates, and less waste is currently held back by a lack of mechanistic information. A particular challenge is the discovery of structure and reactivity trends for the hydride complexes that perform the key HAT step. The proposed project aims to improve the HAT alkene reactions through study of metal-hydrides and radical intermediates in the catalytic cycle of HAT alkene reactions, starting with alkene cross-coupling and continuing to other alkene hydrofunctionalization reactions. The expected outcome of these studies is that the HAT alkene reactions will become possible at or below room temperature, with high chemoselectivity, regioselectivity, and stereoselectivity. This will include the first examples of enantioselective HAT alkene reactions. The PI, Patrick Holland, is an expert in mechanistic studies with paramagnetic iron-alkyl and iron-hydride compounds, and the project will provide rigorous identification of the structures, spectroscopy, reactions and mechanisms that are relevant to the catalytic cycle. A special focus in the first funding period will be the iron-catalyzed reductive cross-coupling of alkenes, where we will leverage our discovery of important but unrealized aspects of the mechanism such as the presence of proton-coupled electron transfer from metal- alcohol species. The lessons learned will be applied to a broad family of radical C-C and C-N bond coupling reactions catalyzed by Mn, Co, and Fe. These advances will make the HAT alkene reactions milder and higher-yielding, will minimize byproducts/waste, and will accommodate a broader range of substrates for preparation of biologically relevant products. The enantioselective versions of the alkene cross-coupling reactions will provide a new route to heavily substituted, stereodefined carbon sites that are useful in natural products and bioactive molecules.